Process and intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds

ABSTRACT

This application discloses a novel process to synthesize 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds, which may be used, for example, as NK-1 inhibitor compounds in pharmaceutical preparations, intermediates useful in said process, and processes for preparing said intermediates; also disclosed is a process for removal of metals from N-heterocyclic carbine metal complexes.

FIELD OF THE INVENTION

This application pertains to processes useful in the preparation of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds and intermediates useful in the synthesis thereof, and theintermediate compounds prepared thereby.

BACKGROUND OF THE INVENTION

Identification of any publication, patent, or patent application in thissection or any section of this application is not an admission that suchpublication is prior art to the present invention.

The preparation of diazaspirodecan-2-ones for example,8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one,for example,(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the compound of Formula I) has been described in U.S. Pat. No.7,049,320 (the '320 patent), issued May 23, 2006, the disclosure ofwhich is incorporated herein in its entirety by reference.

The compounds described in the '320 patent are classified as tachykinincompounds, and are antagonists of neuropeptide neurokinin-1 receptors(herein, “NK-1” receptor antagonists). Other NK₁ receptor antagonistsand their synthesis have been described, for example, those described inWu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, TetrahedronLetters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57,8971-8981 (2001) and in published International Application No.WO05/100358, each of which is incorporated herein in their entirety byreference. A process for preparing the compound of Formula I is alsodisclosed in U.S. Application No. 2008/003640, filed Mar. 20, 2008 (the'640 application).

“NK-1” receptor antagonists have been shown to be useful therapeuticagents, for example, in the treatment of pain, inflammation, migraine,emesis (vomiting), and nociception. Among many compounds disclosed inthe above-mentioned '320 patent are several noveldiazaspirodecan-2-ones, including the compound of Formula I, which areuseful in the treatment of nausea and emesis associated with any sourceof emesis, for example, emesis associated with recovery from anesthesiaor chemotherapy treatments (Chemotherapy-induced nausea and emesis,herein, CINE).

The synthesis method for preparing the compound of Formula I describedin the '320 patent generally follows Scheme A in the provision of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds.

The process for the preparation of the compound of Formula I describedin the '320 patent is carried out in 18 individual steps fromcommercially available starting materials, and in many steps of theprocess described in the '320 patent, intermediate compounds must beisolated or isolated and purified before use in a subsequent step, oftenutilizing column chromatography for that purpose. In general, thesynthetic scheme described in the '320 patent consumes a larger thandesirable percentage of starting and intermediate compounds in theproduction of unwanted isomers.

The process for the preparation of the compound of Formula I describedin the '640 application generally follows Scheme B:

The process described in Scheme B comprises about half the number ofsteps compared to Scheme A and produces the compound in greater yieldthan Scheme A, however, both schemes suffer from poordiastereoselectivity.

Accordingly, what is needed is a more convergent and efficient processwhich has improved diastereoselectivity.

SUMMARY OF THE INVENTION

What is needed is a synthetic scheme for the preparation of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onecompounds which has a reduced number of steps, increasesdiastereoselectivity, and provides a reaction scheme affording practicalscale up to a batch size suitable for commercial scale preparation.

These and other objectives are advantageously provided by the presentinvention, which in one aspect, as illustrated in Scheme I, is a processof making(5S,8S)-8-[{1-(R)-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onehydrochloride monohydrate, the compound of Formula VIII.

wherein the process comprises:

-   -   a) providing the salt compound of Formula VIa,        [5(R)-[[[1(S)-[[1(R)-[3,5-bis(trifluoromethyl)-phenyl]ethoxy]-methyl]-1-phenyl-2-propenyl]amino]methyl]-5-ethenyl-2-pyrrolidinone]        [Salt 2], wherein “Salt 2” represents at least one proton bonded        to a base functional group in the compound of Formula VIa, for        example, a nitrogen electron pair, thus forming an ammonium        cation, and associated therewith a coordinated anion moiety, for        example, the conjugate base of an acid, and cyclizing the        diene-amine salt compound of Formula VIa using a ring closing        metathesis catalyst;    -   b) converting the cyclized product from Step (a) to a salt to        obtain the compound of Formula VII        [(5R,8S)-8-[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethoxymethyl]-8-phenyl-1,7-diazaspiro[4.5]dec-9-en-2-one]        Salt 3, wherein “Salt 3” represents at least one proton bonded        to a base functional group in the compound of Formula VII and        associated therewith a coordinated anion moiety;    -   c) treating from the salt compound of Formula VII provided in        Step (b) with a hydroxide base of Formula M-OH, for example,        wherein “M” is a alkaline metal or alkali earth metal, to        provide the corresponding freebase compound of Formula VIIb,        reducing the freebase compound of Formula VIIb and treating the        reduction product with HCl to obtain the        1,7-diazaspiro[4.5]dec-2-one hydrochloride hydrate of Formula        VIII; and    -   d) optionally recrystallizing the HCl salt of Formula VIII        thereby obtaining the compound of Formula Ia.

In some embodiments of Scheme I, it is preferred to carry out thereduction in Step “c” on the salt compound of Formula VII withoutliberating the freebase form thereform and recovering the reduced saltproduct produced thereby instead of precipitating the salt of thefreebase reduction product.

In some embodiments of the present invention, preferably Step (a) ofScheme I is carried out in the presence of a sufficient amount of addedacid to decrease the loading (amount of catalyst present) of thering-closing metathesis catalyst employed. In some embodiments of SchemeI using added acid in Step (a), it is preferred to use an acid having apKa which is about equal to or less than that of the diene compound ofFormula VI being cyclized in the reaction, for example, an acid having apKa equal to or less than 6.5. In some embodiments of Scheme I employingadded acid in Step (a), it is preferred for the acid to be: (i) amineral acid, for example, HCl, HBr, or sulfuric acid; (ii) a mono- ordi-organic acid, for example, acetic, proponoic, maleic, fumaric,trifluoroacetic, or tartatic acids; or (iii) a sulfonic acid, forexample, an alkylsulfonic acid or substituted alkylsulfonic acid, forexample, methanesulfonic acid, 4-methylbenzenesulfonic acid monohydrate,or trifluoromethanesulfonic acid, or an aromatic arylsulfonic acid, forexample p-toluenesulfonic acid or a substituted arylsulfonic acid. Insome embodiments utilizing an excess acid in Step 2, the acid ispreferably an arylsulfonic acid, more preferably p-tolysulfonic acid. Insome embodiments employing excess acid in Step 2, it is preferred to addthe acid in an amount of from about 0.1 to about 2.0 equivalentsrelative to the amount of substrate initially present in the reactionmixture.

In some embodiments of Scheme I it is preferred to carry out thecyclization reaction in Step (a) by the process illustrated in SchemeIa.

wherein

the dotted line of the compound of Structure XX represents an optionaldouble bond and “Salt 2” is as defined above;

Ar is an aryl moiety, for example, phenyl or mesityl(2,4,6-trimethylphenyl);

L is P(R^(2a))₃, wherein R^(2a) is selected independently and is phenyl,aryl, alkoxylphenyl or alkyl;

M is a metal which is ruthenium, palladium, or iridium;

X is halogen;

R is H, aryl, or heteroaryl; and

HX is an acidic species, preferably where “X” is: halogen, for example,chloride, bromide, or iodide; sulfate; sulfite; or a sulfonate moiety,for example, mesylate, trifluoromethylsulfonate, or an aryl sulfonate,for example tosylate, the process comprising:

-   -   (i) contacting a secondary amine salt of Formula VI with an acid        of the Formula HX;    -   (ii) adding a ring closing metathesis catalyst to the mixture        from step (i), preferably in an amount which is        sub-stoichiometric with respect to the amount of the compound of        Formula VI used; and    -   (iii) heating the mixture to cyclize the compound of Formula VI.

In some embodiments of Scheme Ia, the ring-closing metathesis catalystused in the reaction is preferably selected from the compounds ofFormulae XXa, XXb, or XXd:

where the metal (M) is preferably a transition metal with a formaloxidation state providing 8 “d” orbital electrons (a group 8 transitionmetal, for example, ruthenium, palladium or iridium, or a group 6transition metal, for example, molybdenum), “L¹” is a sigma-bondedcarbon ligand with substantial Pi-backbonding capability, for example,the imidazole ligand shown in the compounds of Formulae XXa and XXd, andL² is a monodentate ligand, for example, a phosphine ligand, for example(Cy₃P), or, as indicated, L² is optionally bonded to the R³ substituentof the carbene (ligand, and when optionally bonded to the carbene ligandvia R³, illustrated by the semicircular dotted line between L² and R³,L² forms a bidentate ligand, and L² is a chelating moiety, for example,an oxygen, phosphorous, or nitrogen moiety, for example, the oxygenmoiety in the alkoxybenzylidene bidentate ligand shown in the catalystof Formula XXd, for example, an isoproxy-benzylidene ligand, R¹ isindependently selected from aryl, heteroaryl, alkyl, or hydrogen, R³ isan alkyl heteroaryl or aryl, for example, a phenyl moiety, or when R³ isnot bonded to L², R³ may be hydrogen, and (X) is a conjugate base of astrong acid, preferably X is a sulfonate moiety, for example, tosylate,or halogen moiety, for example, chloride.

It will be appreciated that in reaction Scheme I shown above, althoughthe compound of Formula Ia is the (S,S,R) enantiomer, the process of theinvention can be employed using starting materials of the appropriatestereoisomer configuration to prepare all of the isomers of the compoundof Formula I, i.e.,

In some embodiments of the invention it is preferred to provide thecompound of Formula VIa used in Scheme I by the process of Scheme Iaa

wherein the process comprises:

-   a) providing the pyrazolo-5-one of Formula III;-   b) providing the freebase compound of Formula IV,    [(1S)-1-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-1-phenylprop-2-enyl)amine,    and reacting it with the compound of Formula III provided in    Step (a) to yield the diene-imine of Formula V,    [((5R)-5-((Z)-{[(1S)-1-({(1R)-1-[3,5-bis(trifluoromethyl)-phenyl]-ethoxy}methyl)-1-phenylprop-2-en-1yl]imino}methyl)-5-vinylpyrrolidin-2-one)];-   c) reducing the diene-imine compound of Formula V prepared in    Step (b) to obtain the corresponding diene-amine compound,    converting it to the corresponding salt compound of Formula VI,    [5(R)-[[[1(S)-[[1(R)-[3,5-bis(trifluoromethyl)-phenyl]ethoxy]-methyl]-1-phenyl-2-propenyl]amino]methyl]-5-ethenyl-2-pyrrolidinone]    [Salt 2], wherein “Salt 2” represents at least one proton bonded to    a base functional group in the compound of Formula VI, for example,    the electron pair in a nitrogen atom in the compound, and associated    therewith a coordinated anion moiety.

In some embodiments of the present invention it is preferred to providethe pyrazolo-5-one compound of Formula III in Step (a) of Scheme Iaa bytreating the compound of Formula II,(3R)-(1,1-dimethylethyl)-7aR-ethenyltetrahydro-1(R/S)-hydroxy-3H,5H-pyrrolo[1,2-c]oxazol-5-one, with an appropriatebase, for example, triethylamine. In some embodiments of the presentinvention it is preferred to provide the free-base compound of FormulaIV in Step (b) of Scheme Iaa by treating the corresponding salt compoundof Formula IVa with a water soluble base, for example, sodium hydroxide,

wherein Salt 1 represents at least one proton bonded to a basefunctional group, for example, the amine substituent, in the compound ofFormula IVa and associated therewith a coordinated anion moiety.Suitable acids for preparing the salt compounds of Formula IVa are, forexample: organic acids, for example, maleic acid, succinic acid, ormalic acid; and inorganic acids, for example, HCl, HBr, and HI.

In some embodiments of the present invention, in Step 2, preferably, thering-closing metathesis catalyst is a ring-closing metathesis catalystof Formula XX, described in Scheme 4 (below).

In some embodiments of the present invention it is preferred to preparethe intermediate of Formula IV using the process illustrated in Scheme2, steps 2-3 and beyond. In some embodiments it is preferred to providethe intermediate of Structure X for use in preparing the compound ofFormula IV as shown in Scheme II, steps 2-1 and 2-2.

wherein the process comprises:Step 2-1:cyclyzing the 2-phenylglycine derivative shown with PhCH(OCH₃)₂ toobtain the oxazolidinone of Formula IX, wherein Cbz is acarboxybenzyl-amine protecting group;Step 2-2:combining the compound of Formula IX with[3,5-bis(trifluoromethyl)phenyl]-ethoxy-bromomethyl ether to obtain thelactone of Formula X;Step 2-3:reducing the lactone of Formula X to the lactol of Formula XI;Step 2-4:opening the ring of the lactol of Formula XI to obtain the aldehyde ofFormula XII;Step 2-5:Converting the aldehyde of Formula XII to the alkenyl amine of FormulaXIII; andStep 2-6:deprotecting the alkenyl amine of formula XIII and converting thecorresponding free base thus obtained to the salt of Formula IV.

In some embodiments of the process of the invention it is preferred toprepare the intermediate of Formula II in accordance with the processillustrated in Scheme 3.

wherein the process comprises:Step 3-1:treating pyroglutamic acid with trimethylacetaldehyde andmethanesulfionic acid to obtain(3R,6S)-3-tert-butyldihydro-1H-pyrrolo[1,2-c][1,3]oxazole-1,5(6H)-dioneof Formula XIV;Step 3-2:reacting the pyrrolo[1,2-c][1,3]oxazole-1,5(6H)-dione of Formula XIVwith methyl formate to obtain the pyrrolo[1,2-c]oxazole-7a-carbaldehydeof Formula XV;Step 3-3:converting the carbaldehyde of Formula XV to the7a-vinyl-dihydro-pyrrolo[1,2-c][1,3]oxazole-1,5-dione of Formula XVI;andStep 3-4:reducing the dione of Formula XVI to obtain the(3R)-1,1-dimethyl-7a(R)-ethenyltetrahydro-1(R/S)-hydroxy-3H,5H=pyrrolo[1,2-c]oxazol-5-oneof Formula II.

Another aspect of the present invention relates to the following novelintermediates used or prepared in the processes represented in Schemes1-3:

Scheme 4 illustrates a chemical process for removing metathesis catalystfrom the reaction mixture after ring closure is complete. In someembodiments of the present invention it is preferred to employ thechemical process illustrated in Scheme 4 at the end of reaction Step 2shown in Scheme 1 to removal of the metal associated with the metathesiscatalyst employed in the cyclization reaction. Accordingly, Scheme 4illustrates removal of a metathesis catalyst of Formula XXa′, preferablythe complex of Formula XXa′ is an N-heterocyclic carbine metal complex,but it will be appreciated that the process can be employed tochemically remove any metal metathesis catalyst from the reactionmixture.

wherein

-   -   the dotted lines represent optional bonds;    -   Ar is phenyl, 2,4,6-trimethylphenyl, or 2,6-dimethylphenyl;    -   M is preferably a transition metal with a formal oxidation state        providing 8 “d” orbital electrons (a group 8 transition metal,        for example, ruthenium, palladium or iridium) or a group 6        transition metal, for example, molybedinum;    -   L² is a phosphine ligand, for example, P(R)₃, where “R” is        phenyl aryl, or alkyl, for example, (Cy)₃P, or optionally, L² is        bonded to the carbene substituent via R³, indicated by the        semicircular dotted line between L² and R³, forming a bidentate        ligand, wherein L² is a chelating moiety, for example, an        oxygen, phosphorous, or nitrogen moiety, for example, the oxygen        moiety in the isoproxy-benzylidene bidentate ligand shown in the        catalyst of Formula XXd (herein),    -   R¹ is independently selected from aryl, alkyl, or hydrogen;    -   R² is H, OH, or ═O;    -   R³ is an aryl, alkyl or phenyl moiety, or H if L² is not bonded        to R³, and    -   (X) is a conjugate base of a strong acid, for example, a        halogen, a sulfate, sulfite or sulfonate anion, preferably “X”        is a sulfonate anion, for example tosylate or a halogen moiety        which is chloride or bromide,        the process comprising:    -   (i) heating a mixture of an aqueous solution of a reducing        reagent, preferably a reducing reagent which is sodium        metabisulfite (Na₂S₂O₅), sodium sulfite (Na₂SO₃), sodium        bisulfite (NaSO₃H), hypophosphorous acid (phosphinic acid,        H₃PO₂), sodium formate (NaOCHO) or phosphorous acid sodium salt        (NaH₂PO₃), or mixtures of two or more, in the presence of a        solution comprising a water-immiscible organic solvent and at        least one N-heterocyclic carbine metal complex of Formula [XX],        [XXa], [XXb] or [XXd]; and    -   (ii) separating the metal complex of Formula ML₂ from the        organic layer after heating Step (i) by: (a) filtration where        the metal complex is insoluble; or (b) where the metal complex        is soluble, uptake of the metal complex into the aqueous layer        and separating the organic and aqueous layers.

In some embodiments it is preferred to carry out the process of Scheme 4in the presence of a phase transfer catalyst, for example a quaternaryammonium salt, for example, a quaternary ammonium salt of the Formula[(R^(a3))₄N]⁺X⁻, wherein R^(a3) is alkyl, for example, n-butyl-, and Xis a halide, sulfonate, or nitrate.

In some embodiments it is preferred to employ as the reducing reagent:(i) one or more inorganic salt compounds, for example, Na₂S₂O₅, Na₂SO₃,or NaH₂PO₃; (ii) a phosphorous acid, for example, H₃PO₂; (iii) one ormore metal hydride compounds, for example, sodium hydride, sodiumborohydride, or lithium aluminum hydride; (iv) a reduction carried outwith hydrogen and a catalyst, for example, palladium on carbon; (v) anorganic reducing reagent, for example, ascorbic and oxalic acids; (vi)hydrogen peroxide; or (vii) one or more metal reducing reagents, forexample, copper, zinc, iron or magnesium. It will be appreciated thatwhile Scheme 4 is illustrated with the metathesis catalyst of FormulaXXa, the process will yield similar results and advantages if used inthe presence of any metathesis catalyst.

Other aspects and advantages of the invention will become apparent fromfollowing Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

Earlier processes for the preparation of the compound of Formula Iinclude preparation of the piperidinyl moiety, followed by reactions toadd the spiro pyrrolidinyl ring, while the presently claimed processcyclizes a3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-1-phenyl-2-propenyl]amino]methyl]-5-ethenyl-2-pyrrolidinone.Compared to previous procedures, the present invention for preparing thecompound of Formula I is convergent and shorter, provides for improvedenantiomeric and diastereomeric selectivity, provides the compound inhigher yield, and is easier and more cost-effective to use.

Terms used in the general schemes herein, in the examples, andthroughout the specification, include the following abbreviations,together with their meaning, unless defined otherwise at the point oftheir use hereinafter: Me (methyl); Bu (butyl); t-Bu (tertiary butyl);Cbz- (Carboxybenzyl); Et (ethyl); Ac (acetyl); t-Boc or t-BOC(t-butoxycarbonyl); DMF (dimethylformamide); THF (tetrahydrofuran);DIPEA (diisopropylethylamine); RT (room temperature, generally 25° C.);TFA (trifluoroacetic acid); TEA (triethyl amine); NMP(1-methyl-2-pyrrolidinone); MTBE or TBME (tert-butyl methyl ether); Me(methyl); Mes, when used as a structural substituent (mesityl, which is2,4,6-trimethylphenyl-moiety); Ph (phenyl); NaHMDS (sodiumhexamethyldisilizane); DMI (1,3-dimethyl-2-imidazolidinone); AcOH(acetic acid);

LHMDS (lithium bis(trimethylsilyl)amide);

TMSCl (chlorotrimethylsilane or trimethylsilyl chloride); TFAA(trifluoroacetic anhydride); and IPA (isopropanol).

As used herein, the following terms, unless otherwise indicated, areunderstood to have the following meanings:

Alkyl means a straight or branched chain aliphatic hydrocarbon having 1to 6 carbon atoms.

Halogen means a halogen moiety, for example, fluoro, chloro, bromo oriodo.

PTC, a phase-transfer catalyst, an agent which facilitates transfer of areactive moiety or reaction product from one phase to another phase in areaction mixture.

A wavy line

appearing on a structure and joining a functional group to the structurein the position of a bond generally indicates a mixture of, or eitherof, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.For example,

means containing either, or both of

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

However, sometimes in the examples herein, the CH₃ moiety is explicitlyincluded in a structure. As used herein, the use of either conventionfor depicting methyl groups is meant to be equivalent and theconventions are used herein interchangeably for convenience withoutintending to alter the meaning conventionally understood for eitherdepiction thereby.

The term “isolated” or “in isolated form” for a compound refers to thephysical state of said compound after being isolated from a process. Theterm “purified” or “in purified form” for a compound refers to thephysical state of said compound after being obtained from a purificationprocess or processes described herein or well known to the skilledartisan, in sufficient purity to be characterizable by standardanalytical techniques described herein or well known to the skilledartisan.

In the reaction schemes depicting the present inventions, bracketsaround a structure indicate that the compound is not necessarilypurified or isolated at that stage, but is preferably used directly inthe next step. Also, various steps in the general reaction schemes donot specify separation or purification procedures for isolating thedesired products, but those skilled in the art will recognize that wellknown procedures are used.

Typical parameters for the process described in Scheme 1 are discussedbelow.

With reference to Scheme I, above, in some embodiments step 1 is typicalcarried out in accordance with the following reaction scheme:

In some embodiments, it is preferred to provide the compound of FormulaIII by carrying out Step 1a, wherein the compound of Formula II isconverted to the compound of Formula III by treatment with a base, forexample, a lower alkyl amine, for example, a tertiary amine, forexample, triethylamine, diisopropylethylamine, or tributylamine, in asolvent that is miscible with water, for example, a lower alcohol (thatis, having from about 1 to about 6 carbon atoms), for example ethanol,methanol, isopropanol, butanol or mixtures thereof, at a temperature offrom about 0° C. to about 80° C., preferably from about 10° C. to about60° C., more preferably from about 20° C. to about 30° C., and for aperiod of from about 3 hours to about 10 hours.

In Step 1b, the compound of Formula III, for example, as the mixturefrom Step 1a, is added to a solution of the free base of Formula IV andheated to react the two. After addition the mixture is heated to refluxand water generated in the reaction is removed via azeotropicdistillation to drive the reaction. In some embodiments, the freebase ofFormula IV is prepared from a salt of Formula IVa by treating the saltof Formula IVa with a water soluble base, for example, NaOH dissolved ina low polarity solvent, for example, toluene or a non-polar solvent, forexample, xylenes, or mixtures of the two.

In some embodiments, in Step 1c, it is preferred to reduce the productof Step 1b is with a source of hydride, for example, metal hydridereducing reagents, for example, sodium borohydride, sodiumcyanoborohydride, or sodium triacetoxyborohydride, in the presence of anacid, for example, acetic acid, trifluoroacetic acid, phosphoric acid,methanesulfonic acid or trifluoromethanesulfonic acid and mixturesthereof to obtain the free base of Formula VI. In some embodiments it ispreferred to carry out the reaction in toluene, acetonitrile,1,2-dichloroethane, tetrahydrofuran, ethyl acetate, isopropyl acetate,or mixtures of two or more thereof. In some embodiments it is preferredto carry out the reaction at a temperature of from about 0° C. to about80° C., preferably from about 10° C. to about 60° C., more preferablyfrom about 15° C. to about 25° C. In some embodiments it is preferred tocarry out the reaction for a period of from about 2 hours to about 10hours. After obtaining a free base of Formula VI, it is converted (step1c′) to a salt compound of Formula VIa by treatment with an acidreagent, for example, p-toluene sulfonic acid, methanesulfonic acid,trifluoromethanesulfonic acid, trifluoroacetic acid, HCl, HBr, orsulfuric acid. In some embodiments it is preferred to carry out theconversion to a salt compound of Formula VIa in a water-misciblesolvent, for example, alkyl alcohol having from about 1 to about 6carbon atoms, for example, methanol, ethanol, propanol, isopropanol, orbutanol and its isomers, or a mixture of two or more thereof, andthereafter isolate the salt product.

In Step 2, the salt compound of Formula VIa is converted to a free base,which is then cyclized with a ring closing metathesis catalyst, and theresultant product is converted again to a salt and isolated.

The ring closing metathesis catalysts are preferably those containing ametal with a carbene ligand, for example, the catalyst of Formula XX:

where the metal (M) is preferably a transition metal with a formaloxidation state providing 8 “d” orbital electrons (a group 8 transitionmetal, for example, ruthenium, palladium or iridium) or a group 6transition metal, for example, molybdenum; (X) is a conjugate base of astrong acid, preferably X is: a sulfonate moiety, for example, tosylate;or halogen moiety, for example, chloride; (L¹) is a sigma-bonded carbonligand with substantial Pi-backbonding capability, for example, as shownin the catalyst of Formula XXa, an imidazolidine ligand

(wherein Ar is an aryl moiety, for example benzyl, phenyl or mesityl(2,4,6-trimethyl phenyl) moiety), L² is a phosphine ligand, for example(Cy₃P), or, as indicated, L² is optionally bonded to R³, illustrated bythe semicircular dotted line between L² and R³, when L² is bonded to thecarbene moiety via R³, it forms a bidentate ligand, and L² is achelating moiety, for example, an oxygen, phosphorous, or nitrogenmoiety, for example, the oxygen moiety in the isoproxy-benzylidenebidentate ligand shown in the catalyst of Formula XXd, R¹ isindependently selected from aryl, alkyl, or hydrogen, and R³ is an alkylor phenyl moiety, or when R³ is not bonded to L², R³ may be hydrogen.

Suitable ring-closing metathesis catalysts are commercially available,for example: (i) the catalysts described as “Grubbs' First generationcatalyst” in U.S. Pat. No. 6,215,019 and that described as “Grubbs'Second Generation catalysts” in published PCT Application Nos. WO99/51344 and WO 00/71554 and the catalysts described as “Hoveyda-Grubbs'First and Second Generation catalysts” in published PCT Application No.PCT/US01/24955, both available from Materia; (ii) Zhan's catalystdescribed in published international application publication no. WO2007/003135), available from Zannan Pharma; and (iii) Grela's catalystdescribed in published international application publication no.W)2004/035596, available from Boehringer-Ingelheim. In some embodimentsof the present invention it is preferred to use a catalyst having: (i) achelating isoproxybenzylidene ligand; and (ii) abismestiylene-substituted N-heterocyclic carbene ligand, for example,the Hoveyda-Grubbs' Second Generation Catalyst.

In some embodiments it is preferred to employ a catalyst of the formula:

In some embodiments it is preferred to employ a catalyst of the formula:

where R⁴ is “H—”, a nitro moiety (—NO₂), or a sulfonamide moiety(—SO₂N(R⁵)₂, wherein R⁵ is an alkyl moiety of 10 carbon atoms or less).

With reference to Scheme 1, Step 2, in some embodiments it is preferredto use a reaction mixture loading of the ring-closing metathesiscatalyst (catalyst loading) in an amount of from about 100 mol % toabout 0.1 mol %, more preferably the catalyst is used in an amount offrom about 20 mol % to 0.1 mol %, and more preferably about 10 mol % toabout 0.5 mol %, relative to the amount of the compound of Formula Vinitially present in the reaction mixture. As mentioned above, theaddition of acid to the reaction mixture in Step 2, for example,4-methylbenzenesulfonic acid monohydrate or toluenesulfonic acid, canreduce the reaction mixture catalyst loading required to achievecomplete, or nearly complete, conversion of the substrate under givenreaction conditions. Table I, below, illustrates the results obtained byadding various amounts of p-toluenesulfonic acid to the reaction mixtureand observing the amount of substrate conversion as a function ofcatalyst loading with and without added acid. In some embodiments whereacid is added to reduce catalyst loading it is preferred to add acid inan amount of from about 0.01 equivalents (eq.) to about 2 equivalents(eq.) relative to the amount of substrate initially present in thereaction mixture, more preferably, acid is added in an amount of fromabout 0.1 eq. to about 1.8 eq., and more preferably acid is added in anamount of from about 0.2 eq. to about 1.5 eq. relative to the amount ofsubstrate initially present in the reaction mixture.

Without wanting to be bound by theory, the inventors believe that bestresults respecting the use of added acid in Step 2 for the reduction ofcatalyst loading will be achieved by adding to the reaction mixture anacid possessing a pKa≦6.5, which is the calculated pKa of intermediateIV. Various types of acid are believed to be useful for reducing therequired catalyst loading to achieve high conversion of the substrate,for example, but not limited to: (i) mineral acid, for example HCl, HBr,HI, phosphoric acid, or sulfuric acid or mixtures thereof; and (ii)organic acid, for example, acetic acid, trifluoroacetic acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid,halogen-substituted benzenesulfonic acid, or heteroaromatic sulfonicacid, or mixtures thereof.

TABLE I Conversion vs. Catalyst Loading vs. TsOH Charged CatalystLoading Additional TsOH Added Reaction Conversion (mol %) (mol %) (% ofVII/Vl) 5 0 85-90  5.5-7 0 90-100 >7 0 100 1 20 57 5 20 100 3 60 100 560 100 5 100 100 2 100 93-100 1 100 88 1.5 150 98-100 1 150 98 0.5 15076 1 200 44

With reference to Table I, cyclization reactions in accordance with Step2 of Scheme I (above) were run employing from 0 to about 2 moleequivalents (eq.) of added acid relative to the amount of substrate tobe cyclized. These data show that adding acid to the reaction mixture inStep 2 can reduce by a factor of more than 4.5 the catalyst loadingrequired in the reaction mixture to achieve a high percentage conversionof the substrate. Accordingly, where loadings of 7 mol. % or more wereneeded to achieve nearly 100% substrate conversion without added acid,conversions approaching 100% of substrate could be achieved using acatalyst loading of 1.0 mol. % in conjunction with 150 mol. % additionalacid in the reaction mixture.

In some embodiments it is preferred to carry out the ring-closingreaction of Step 2 in an anhydrous, degassed (for example, using N₂)reaction medium comprising a non-coordinating medium polarity solvent,for example, toluene, trifluorotoluene, chlorobenzene, benzene,xylene(s), chloroform, dichloromethane, or dichloroethane. In general,the reaction is carried out at atmospheric pressure or a pressureslightly elevated above atmospheric pressure. In some embodiments it ispreferred to carry out the ring-closing metathesis reaction bydissolving the catalyst in a solvent which is the same as, or similarto, the reaction solvent and adding the catalyst solution slowly over aperiod of about 30 minutes while maintaining the temperature of thereaction mixture within a temperature range of from about 20° C. toabout 100° C., preferably from about 30° C. to 90° C. and morepreferably from about 60° C. to about 80° C.

In some embodiments, at the end of the cyclization reaction it ispreferred to remove the metal from the catalyst using the processdescribed in Scheme 4, i.e., the product of the ring-closing procedureis treated with an aqueous solution of a reducing reagent and theresultant metal species is extracted into the aqueous layer. Suitablereducing reagents include, but are not limited to, inorganic reagents,for example, sodium bisulfite, sodium metabisulfite, sodium thiosulfite,sodium formate, sodium borohydride and its derivatives.

In some embodiments employing the process of Scheme 4 to remove metalfrom the metathesis catalyst, it is preferred to employ also in thereaction mixture a phase transfer catalyst (PTC) in an amount of fromabout 0.05 mol % of PTC relative to the amount of reducing reagentemployed to about 200 mol % of PTC relative to the amount of reducingreagent employed, preferably PTC is employed in an amount which is fromabout 0.1 mol % to about 100 mol % relative to the amount of reducingreagent employed. Suitable phase transfer catalysts for use in theprocess include, but are not limited to, quaternary ammonium salts ofthe Formula (R*₄N⁺X⁻) wherein “R*” is an alkyl group, as defined herein,and “X” is an anion, preferably “X” is Cl⁻, Br⁻, I⁻, F⁻, or NO₃ ⁻. Theinventors have surprisingly found that when the process is carried outin the presence of a suitable phase transfer catalyst, the PTC permitsthe reduction to proceed to completion at either a lower temperature,for example, as low as 25° C., within a shorter period of time, forexample, in less than 1 hour, or depending upon the temperature regimeselected, both the reaction period and the reaction temperature can bereduced over that required to achieve a complete reduction in theabsence of a phase transfer catalyst.

In some embodiments it is preferred to convert the cyclized product fromwhich the catalyst has been removed to a salt by treatment of thereaction mixture containing the cyclized product with a reagentcomprising: (i) a mineral acid, for example, HCl, HBr, HI, H₃PO₄, orH₂SO₄; (ii) an organic acid or substituted organic acid, for example,Maleic Acid, Fumaric Acid, Tartaric Acid or trifluoroacetic acid; (iii)a sulfonic acid or substituted sulfonic acid, for example,methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonicacid, p-Toluenesulfonic acid, or p-nitrobenzenesulfonic acid. In someembodiments it is preferred to prepare the HCl salt of the compound ofFormula VI.

With reference to Scheme I, in Step 3, the salt of Formula VII isconverted to the free base form. In some embodiments it is preferred toaccomplish the conversion by treating the compound of Formula VII with abase, for example, NaOH, KOH, NaOR (where “R” is an alkyl groupcontaining from about 1 to about 12 carbon atoms). In some embodimentsthe conversion of the compound of Formula VII in Step 3 is carried outin a reaction solvent comprising a low polarity organic solvent, forexample, toluene, Xylene, ethers (for example, diethyl ether and methylt-butyl ether), to obtain the free base of VII, and subsequently reducethe free base to the compound of Formula VIII by hydrogenation, forexample by treatment with hydrogen in the presence of a hydrogenationcatalyst, for example, palladium on carbon, platinum on carbon,palladium oxide, ruthenium, or Wilkinson's catalyst, or mixturesthereof. In some embodiments it is preferred to carry out Step 3 in alow polarity, organic solvent, for example, toluene or Xylene, or in apolar organic solvent, for example alcohols (C1 to C12 linear orbranched alkyl), or ethers, or in water, or a mixtures of two or morethereof. In some embodiments, after the hydrogenation reduction iscomplete, the catalyst employed in Step 3 is removed from the reactionmixture, for example, by filtration, and the product compound in thereaction mixture is then treated with an acid to make the correspondingsalt, for example, in embodiments where the product compound is treatedwith HCl at this step, the compound of Formula VIII (Scheme I) isobtained as the hydrochloride hydrate.

The inventor's have surprisingly found that alternatively, withreference to Scheme I, above, the tetrahydropyridine salt compound ofFormula VII can be directly reduced to yield the correspondingamine-salt compound. When the compound of Formula VII is a hydrochloridesalt, reduction of the salt compound of Formula VII yields thehydrochloride hydrate compound of Formula VIII directly without havingto generate the intermediate free-base form of the tetrahydropyridine,the compound of Formula VIIb. In some embodiments employing directreduction of the tetrahydropyridine salt compound of Formula VII,preferably after the reduction reaction is complete, the catalystemployed in the reduction is removed from the reaction mixture bymechanical means, for example, by filtration, and the resultant aminesalt is recovered from the filtrate.

For carrying out the reduction of a salt compound of Formula VIIdirectly without first providing the free-base form of thetetrahydropyridine, the inventors have surprisingly found that thereaction is preferably carried out in a solvent which is: (i) a lowpolarity organic solvent, for example, toluene or xylene or a mixturethereof; (ii) a polar organic solvent, for example, alcohols comprisingfrom about 1 carbon atom to about 12 carbon atoms or a mixture of two ormore thereof; (iii) organic ethers comprising from about 2 to about 12carbon atoms or a mixture of two or more thereof; and (iv) water, ormixtures of any two or more thereof.

Suitable methods for reducing the salt-form of the tetrahydropyridinecompound to the corresponding cyclohexylamine include treatment of thecompound of Formula VII with hydrogen in the presence of a hydrogenationcatalyst Suitable hydrogenation catalysts include, for example,palladium on carbon, palladium oxide, platinum on carbon, ruthenium andWilkinson's catalyst or mixtures of two or more thereof.

In some embodiments, following Step 3 of Scheme I, it is preferred tocarry out Step 4, recrystallizing the product of Step 3 from analcohol/water solution, thereby providing a desirable crystalline formof the compound of Formula Ia. Suitable alcohol solvents useful incarrying out Step 4 include, but are not limited to, alcohols havingfrom about 1 to about 12 carbon atoms, or a mixture of two or morethereof. Alternatively to recrystallization, the compound of FormulaVIII can be suspended in toluene, the suspension extracted with aqueousNaOH, and then treated with HCl to precipitate compound of Formula Ia.

As mentioned above, in some embodiments of the present invention it ispreferred to prepare the intermediate of Formula IV using the processillustrated in Scheme 2. In some embodiments employing the process ofScheme 2 to provide the compound of Formula IV, it is preferred to usethe conditions and parameters illustrated below in Scheme 2ab incarrying out Scheme 2.

In the process of Scheme 2ab, Steps 2-1 to 2-3 are described in theabove-mentioned U.S. Pat. No. 7,049,320 (the '320 patent) the Examples,columns 43 to 44, compounds 1 to 3, and removal of thetriphenylphosphine oxide resulting from carrying out step 2-5.1 shown inScheme 2ab is described on pages 4 to 5 of European publishedapplication No. EP 0850902.

In some embodiments it is preferred to carry out Step 2-4 of Scheme 2abusing a base, for example, KHCO₃ or NaHCO₃ in a solvent, for example,NMP water, a mixture of acetonitrile and water, or a mixture of acetoneand water. In some embodiments it is preferred to stir the reactionmixture while maintaining the reaction mixture at a temp of from about0° C. to about 60° C., preferably from about 5° C. to about 50° C., morepreferably from 15° C. to about 25° C., and after a period of agitation,heat the reaction mixture up to a temperature of less than about 90° C.,preferably to a temperature of less than about 70° C., more preferably,of from about 45° C. to about 55° C., followed by cooling the reactionmixture to ambient temperature (typically about 25° C.) and extractedthe ambient temperature reaction mixture with an organic solvent, forexample, methyl t-butyl ether (MTBE), ethyl acetate, isopropyl acetate,toluene, Xylene or a mixture of two or more thereof.

With further reference to Scheme 2ab, Step 2-5 is carried out by addingthe product of Step 2-4 to a mixture of Ph₃PCH₃X (X=Cl. Br, or I) andsodium or lithium hexamethyldisilizane or lithium diisopropylamide,sodium or potassium alkoxide in an organic solvent for example, toluene,THF, MTBE at a temperature range from −20 to 60° C., preferably from 5to 40° C., more preferably from 10 to 25° C. The reaction mixture iswarmed to room temperature and stirred, then cooled to range from −30 to40° C., preferably from −20 to 30° C., more preferably from −10 to 20°C., and quenched with dilute acetic acid and washed with sodiumbicarbonate solution. The product is treated with MgCl₂ and stirred atroom temperature, then treated with silica gel. Filtration of solidgives the compound of Formula XIII.

In step 2-6, the crude product Formula XIII is treated with TMSI(iodotrimethylsilane) and quenched with an alcohol having from about 1to about 12 carbon atoms, thereby providing (with reference to Scheme I,step 1b) the free base of Formula IV. As illustrated in Step 2-6 ofscheme 2ab, the free base of Formula IV provided is treated with anacid, for example, maleic acid, hydrochloric acid, and hydrobromic acid,to form the corresponding salt, preferably maleic acid is used, therebyproviding the corresponding maleate salt compound of Formula IVa. Insome embodiments, it is preferred to crystallize the salt therebyprovided from toluene and an anti solvent, for example, hexane, heptaneor octane, to provide a crystalline form of the salt.

As mentioned above, in some embodiments of the present invention it ispreferred to prepare the intermediate of Formula II using the processillustrated in Scheme 3. In some embodiments employing the process ofScheme 3 to provide the compound of Formula II, it is preferred to usethe conditions and parameters illustrated below in Scheme 3ab incarrying out Scheme 3.

With reference to Scheme 3ab, in some embodiments it is preferred tocarry out Step 3-1 using one of several methods:

-   -   a) refluxing pyroglutamic acid with diethylene glycol dimethyl        ether, trimethylacetaldehyde and a strong acid, for example        methanesulfonic acid; or    -   b) heating pyroglutamic acid with trimethylacetaldehyde and a        strong acid, for example, methanesulfonic acid; or    -   c) refluxing pyroglutamic acid with hexamethyl disilizane, then        reacting the product with trimethylacetaldehyde and        methanesulfonic acid; or    -   d) heating pyroglutamic acid and triethylamine with        chlorotrimethylsilane, and then reacting the product with        trimethylacetaldehyde and a strong acid, for example,        methanesulfonic acid; or    -   e) adding trifluoroacetic anhydride to a mixture of pyroglutamic        acid, trimethylacetaldehyde and a strong acid and maintaining        the temperature from about 50° C. to about 100° C. until the        reaction is complete.

In method (a), the compound of Formula XIV is prepared by refluxingpyroglutamic acid in diethylene glycol dimethyl ether solvent, in thepresence of trimethylacetaldehyde and a strong acid. In some embodimentsit is preferred for the strong acid to be trifluoroacetic acid,phosphoric acid, sulfuric acid, methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid or p-nitrobenzenesulfonic acid. In some embodiments of method (a)refluxing with pyroglutamic acid is carried out in the presence of aco-solvent, for example, toluene, Xylene, cyclohexane, THF, or a mixtureof two or more thereof, at refluxing temperature employing a Dean Starkwater-removal apparatus on the refluxing apparatus until the reaction iscomplete.

In method (b), a mixture of pyroglutamic acid with trimethylacetaldehydeand a strong acid, without the diethylene glycol dimethyl ether solventused in method (a) is heated in an apparatus permitting, water removal,for example, a Dean Stark water-removal apparatus. In method (b), as inmethod (a), in some embodiments it is preferred to select as a strongacid trifluoroacetic acid, phosphoric acid, sulfuric acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid or p-nitrobenzenesulfonic acid. In someembodiments the mixture is heated to reflux, typically from about 100°C. to about 120° C., while water is azeotropically distilled off throughthe trap, and reflux is continued until water removal is complete. On abench-scale equipment this is typically accomplished in about 14.5hours.

In method (c), pyroglutamic acid and hexamethyl disilizane in a solventwhich is preferably dioxane, diglyme, toluene or N-methylpyrolidinone(NMP) are heated to reflux for a period of from about 6 hours to about12 hours. Trimethylacetaldehyde and a strong acid, for example,trifluoroacetic acid, phosphoric acid, sulfuric acid, methanesulfonicacid, trifluoromethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid or p-nitrobenzenesulfonic acid are added to theproduct, and the resultant mixture is heated to 90° C. for a period offrom about 4 hours to about 12 hours.

In method (d), chlorotrimethylsilane is added to a mixture ofpyroglutamic acid and triethylamine in toluene while keeping thetemperature under 30° C., and then the mixture is heated to reflux untilthe silylation is completed. The resultant trimethylsilyl-protectedcompound is added to a solvent, for example, N-methyl-2-pyrrolidone, oracetonitrile and treated with trimethylacetaldehyde and a strong acid,for example, trifluoroacetic acid, phosphoric acid, sulfuric acid,methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid or p-nitrobenzenesulfonic acid, maintainingthe temperature of the reaction mixture in a temperature range of fromabout 50° C. to about 100° C., preferably from about 60° C. to about 90°C., more preferably, from about 70° C. to about 85° C. until thereaction is complete, typically a period of from about 18 hours to about24 hours.

In method (e), a mixture of pyroglutamic acid, trimethylacetaldehyde,and a strong acid is prepared and trifluoroacetic anhydride is added toit. In some embodiments the strong acid is selected from: organic acid,for example, trifluoroacetic acid; mineral acid, for example, phosphoricacid or sulfuric acid; sulfonic acid, for example, methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid or p-nitrobenzenesulfonic acid. In some embodiments it is preferredto carry out the reaction in an organic solvent, for example, toluene orN-methyl-pyrrolidone. In some embodiments it is preferred to maintainthe reaction mixture at a temperature of from about 70° C. to about 95°C., more preferably the temperature is maintained at from about 80° C.to about 95° C. In general the reaction mixture is maintained in thedesired temperature range until the reaction is complete, typicallyabout 5 to about 10 hours.

In Step 3-2, the compound of Formula XIV is mixed with: (i) a solventwhich is preferably 1,3-dimethyl-2-imidazolidinone (DMI) ortetrahydrofuran, (ii) methyl formate or ethyl formate; and (iii)optionally a Lewis acid, for example, CuCl or ZnCl₂. When a Lewis acidis employed, typically the Lewis acid is added in amounts of up to about1 eq. relative to the amount of the compound of Formula XIV employed. Insome embodiments a Lewis acid is employed in this step to increase yieldand simplify workup of the reaction mixture. Following the addition ofthe constituents, the reaction mixture is cooled to a temperature offrom about [−100]° C. to about [−55]° C., then, maintaining thetemperature of the reaction mixture, to the reaction mixture is addedlithium bis(trimethylsilyl)amide (LiHMDS) followed bychlorotrimethylsilane (TMSCl). After addition is complete, the reactionmixture is warmed to a temperature of from about 0° C. to about [+10]°C. and combined with an aliquot of a citric acid or acetic acidsolution. The resultant intermediate is treated with trifluoroaceticacid to obtain the pyrrolo[1,2-c]oxazole-7a-carbaldehyde of Formula XV.

In Step 3-3, the carbaldehyde of Formula XV is converted to the7a-vinyl-dihydro-pyrrolo[1,2-c][1,3]oxazole-1,5-dione of Formula XVI bya Wittig reaction, for example by treating it withmethyltriphenylphosphonium halide (Halide=Cl. B, or I) and sodium orlithium hexamethyldisilizane or lithium diisopropylamide, sodium orpotassium alkoxide in an organic solvent, preferably toluene, THF, orMTBE, at a temperature range from about [−20]° C. to about [+60]° C.,preferably from about [−10]° C. to about [+30]° C., more preferably fromabout [+5]° C. to about [+15]° C., then the reaction mixture is quenchedby adding NaCl and acetic acid. The product is treated with MgCl₂ andthe MgCl₂-triphenylphosphine oxide complex thus formed is separated fromthe reaction mixture by filtration. The product remaining in thereaction mixture is crystallized from toluene and heptane to give thecompound of Formula XVI.

In Step 3-4, the compound of Formula XVI is dissolved in an ethersolvent which is preferably tetrahydrofuran or MTBE, or in a lowpolarity organic solvent, for example, toluene. The reaction mixture ismaintained at a temperature of from about [−40]° C. to about 0° C.,preferably at a temperature of from about [−30]° C. to about [−5]° C.,more preferably at a temperature of from about [−25]° C. to about [−15]°C., and then the reaction mixture is treated with lithiumtri(t-butoxy)aluminum hydride, lithium aluminum hydride, or Lithiumdiisobutylaluminium hydride and the temperature is raised to atemperature of from about [−10° C. to about [+10]° C. over a period offrom between about 10 hours to about 16 hours and maintained until thereaction is complete. When the reaction is completed, the reactionmixture is quenched with an acetate solvent, which is preferably ethylacetate, methyl acetate, or isopropyl acetate, and then contactedconsecutively with aliquots of an acid, preferably glacial acetic acidor trifluoroacetic acid, and then an aliquot sodium sulfate decahydrateto obtain the compound of Formula II.

For the intermediate compounds claimed per se, i.e.

In some embodiments it is preferred to isolate compound IV as either amaleate salt, including hydrates thereof, or as a hydrochloride salt,including hydrates thereof. In some embodiments the compounds ofFormulae VI and VII are preferably isolated as a hydrochloride salt or a4-methyl-benzenesulfonic acid salt, more preferably the hydrate of a4-methyl-benzenesulfonic acid salt.

As mentioned above, at the conclusion of Step 2 of Scheme 1, the processillustrated in Scheme 4, above, can be employed to remove metal from thereaction mixture of a ring closing metathesis reaction, allowing themetal to be recycled and providing the product intermediate compoundsubstantially free of contamination from the metathesis catalyst.

With reference to Scheme 4, illustrated above herein, the inventors havesurprisingly found that the metathesis catalyst can be removed from thereaction mixture when the ring-closing reaction is complete by treatingthe reaction mixture containing the metathesis catalyst with a reducingreagent that reacts with the metathesis catalyst. The process describedin Scheme 4 comprises reducing the catalyst in the reaction mixturewhich comprises a water-immiscible solvent by contacting the reactionmixture with an aqueous solution containing a reducing reagent, wherein,the reduction product of the metathesis catalyst is either soluble inthe aqueous layer, and thus is physically separated from the organiclayer using the immiscibility of the two layers, for example, byseparation or decantation, or is insoluble in either the organic oraqueous layer, and thus physically separated from the reaction mixtureby filtration.

For carrying out the metathesis reduction reaction described in Scheme4, above, suitable reducing reagents include: (i) one or more inorganicsalt compounds, which are Na₂S₂O₅, Na₂SO₃, NaSO₃H, NaOC(O)H, or NaH₂PO₃;(ii) a phosphorous acid, for example, H₃PO₂; (iii) one or more metalhydride compounds, for example, sodium hydride, sodium borohydride, orlithium aluminum hydride; (iv) hydrogen in the presence of a reductioncatalyst, for example, palladium on carbon; (v) an organic reducingreagent, for example, ascorbic and oxalic acids; (vi) hydrogen peroxide;or (vii) one or more metals capable of carrying out a reductionreaction, for example, copper, zinc, iron or magnesium.

In some embodiments it is preferred to include in the reaction aninorganic salt compound which can function in the reaction as a phasetransfer catalyst (PTC), for example, a quaternary ammonium salt, forexample (CH₃(CH₂)₃)₄N⁺X⁻, wherein X is preferably a chloride, bromide,iodide, fluoride, bisulfate (HSO₄ ⁻), sulfate (SO₄ ⁻²), or nitrateanion. The inventors have found surprisingly that including a PTC canpermit the reaction to be carried out at a temperature of as low asabout 20° C., whereas, without a PTC the reaction required a temperatureof about 40° C. to proceed. Moreover, the presence of a PTC in thereaction can significantly reduce the time required to complete thereaction at a particular temperature, for example, reducing to a periodof about 6 minutes a reaction requiring a reaction time for a particulartemperature of about 1 hour.

Accordingly, in some embodiments utilizing the reaction process ofScheme 4 to remove the metathesis catalyst used for ring-closure in thesynthesis, it is preferred to employ, as a water-immiscible solventcomprising the reaction mixture toluene, trifluorotoluene,chlorobenzene, benzene, xylene(s), dichloromethane, or dichloroethane ormixtures of two or more thereof. In some embodiments utilizing thereaction process of Scheme 4 to remove the metathesis catalyst used forring-closure in the synthesis, it is preferred to carry out thereduction reaction at a temperature of from about 20° C. to about 100°C. In some embodiments utilizing the reaction process of Scheme 4 toremove the metathesis catalyst used for ring-closure in the synthesis,it is preferred to run the reaction for a period of from about 0.1 hourto about 24 hours. Generally, when this method is employed to remove themetathesis catalyst, the reaction is continued until all of themetathesis catalyst has been reduced. At the end of the reductionreaction the reduced metal, typically in the form of an ML₂ complex, iseither soluble, and so in the course of the reaction is extracted intothe aqueous solution comprising the reducing reagent, or is insoluble ineither the organic or aqueous layers, and therefore precipitates fromthe organic and aqueous mixture.

In some embodiments utilizing the reaction process of Scheme 4 to removethe metathesis catalyst used for ring-closure in the synthesis, where“M” of the metathesis catalyst, for example, the metathesis catalyst ofFormula XXa, is ruthenium, it is preferred to employ Na₂S₂O₅, Na₂SO₃ orPd on carbon in the presence of hydrogen as the reducing reagent. Insome embodiments utilizing the reaction process of Scheme 4 to removethe metathesis catalyst used for ring-closure in the synthesis, where“M” of the metathesis catalyst, for example, the metathesis catalyst ofFormula XXa, is ruthenium, it is preferred to include also a PTC asdescribed above, more preferably, in processes wherein “M” of themetathesis catalyst is ruthenium, it is preferred to employ[(CH₃(CH₂)₃)₄N⁺(HSO₄ ⁻)] or [(CH₃(CH₂)₃)₄N⁺]₂(SO₄ ⁻²)] as the phasetransfer catalyst.

It will be appreciated that the novel method presented above forseparating a metathesis catalyst from the reaction mixture at the end ofthe reaction can be used to cleanly remove a metal metathesis catalystfrom other reactions employing such catalysts so long as the reductionproduct containing the metal is either insoluble in the mixed-phasereaction product obtained after reduction or is soluble in the aqueousphase of the mixed-phase reaction product.

There follows examples illustrating the processes of the invention.Unless otherwise specified, all reagents are articles of commerce,laboratory grade, and used as received.

Example 1

Preparation of[(1S)-1-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-1-phenylprop-2-enyl]amine,monomaleate Step 1

To a solution of the compound of Formula XI (prepared as described in WO2003/054840) (100.0 g, 154.9 mmol) in NMP (200 mL) at RT weresequentially added KHCO₃ (4.6 g, 45.9 mmol) and water (3 mL, 166.7mmol). The resulting mixture was stirred vigorously for 16 h at 20° C.The temperature was then raised to 50° C. and the reaction was stirredfor another 2 h. After the reaction was cooled back to RT, 200 mL ofwater was added. The resulting solution was extracted with TBME (2×200mL). The combined organic layers were sequentially washed with asolution of 14% NaHSO₃ and 7% AcOH in water (2×100 ml), a saturated aq.NaHCO₃ solution, and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuum. The crude compound of Formula XIIwas carried through to the next stage without further purification.

¹H NMR (DMSO-d₆, 600 MHz) δ 9.53 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H),7.89 (s, 1H), 7.34 (m, 10H), 5.09 (dd, 2H), 4.72 (dd, 1H), 4.03 (d, 1H),3.90 (d, 1H), 1.34 (d, 3H).

Step 2

To a slurry of Ph₃PCH₃Br (78.0 g, 217.0 mmol) in toluene (200 mL) wasadded NaHMDS (13% in toluene, 306 g, 217 mmol) slowly at −15° C. Afterslurrying the resulting mixture for 1 h, the crude product from step 1was added slowly. The reaction was then warmed up to RT and stirred foran additional hour. After cooling to 0° C., the reaction was quenchedwith 6% AcOH water solution (400 mL) and washed with a saturated aqueousNaHCO₃ solution. The organic layer was then treated with MgCl₂ (25 g,263 mmol) and stirred for 3 h at RT. After filtration, the organic layerwas treated with silica gel (100 g) and stirred for 30 min. Afterfiltration, the solid was washed with toluene (2×100 mL). The filtrateswere collected and concentrated in vacuum to give the crude product ofFormula XIII in toluene, which was carried through the next step withoutfurther purification. ¹H NMR (CDCl3, 400 MHz) δ 7.59, (1H, s), 7.38 (2H,s), 7.10-7.22 (10H, m), 6.15-6.22 (1H, dd), 5.50 (1H, s), 5.17 (1H, d),5.02 (1H, d), 4.91 (2H, dd), 4.33 (1H, q), 3.65 (1H, broad), 3.48 (1H,broad), 1.26 (3H, d).

Step 3

To the solution of the product of step 2 in toluene (300 mL), was addedtrimethylsilyl iodide (21 mL, 152.4 mmol) slowly. The resulting reactionmixture was stirred for 3 h.

The reaction was then quenched with MeOH (12.4 mL, 305 mmol) and washedsequentially with 15% aq. NaHSO₃ (200 mL) followed by saturated aq.NaHCO₃ (200 mL). The organic layer containing the crude product of thefree base of Formula XIII was carried through to the next stage withoutfurther purification.

Step 4

To the above crude product of step 3 in toluene was added maleic acid(18 g, 155 mmol) dissolved in MeOH (50 mL). The resulting mixture wasstirred for 1 h. The volume of the resulting solution was then reducedto 100 mL at 40° C. under vacuum distillation. At 40° C., n-heptane (100mL) was added to the resulting solution. Upon cooling to RT,crystallization of the maleate salt occurred and additional n-heptane(500 mL) was added. After stirring 2 h, the solid was filtered andwashed with toluene (400 mL), n-heptane (200 mL) and water (250 mL). Thewet cake was dried at 45° C. under vacuum for 12 h to give the compoundof Formula IVa (61 g; 77% yield from 619734-D). MP. 135° C.-140° C. ¹HNMR (DMSO-d₅, 600 MHz) δ 8.87 (s, 2H), 7.94 (s, 1H), 7.90 (s, 2H), 7.45(t, 1H), 7.41 (t, 2H), 7.37 (d, 2H), 6.16 (dd, 1H), 6.06 (s, 2H), 5.47(d, 1H), 5.36 (d, 1H), 4.83 (q, 1H), 3.97 (d, 1H), 3.83 (d, 1H), 1.43(d, 3H). ¹³C NMR (DMSO-d₆, 500 MHz)

167.5, 146.6, 137.4, 136.4, 136.0, 130.8, 130.5, 130.3, 130.0, 128.5,128.3, 126.9, 126.6, 126.1, 124.4, 122.3, 121.2, 120.1, 117.9, 76.6,71.8, 62.1, 22.9. LC-MS exact mass calculated for [C₂₀H₂₀F₆NO⁺]calculated: 404.14436, found: 404.14456.

Example 2

[(1S)-1-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-1-phenylprop-2-enyl]amine,hydrochloride monohydrate

To the solution of the crude product Step 3 from Example 1 (free base)in toluene was added conc. HCl (13 mL, 156 mmol, 37% in water). Afterstirring for 1 h, the volume of the resulting mixture was reduced to 200mL at 40° C. under vacuum distillation and then water (6.6 mL, 465 mmol)was added. After cooling to RT, n-heptane (700 mL) was added slowly. Theresulting slurry was stirred at RT for 6 h, then cooled to 0° C., andstirred for an additional 6 h. The product was filtered, washed withn-heptane (200 mL) and dried at RT under vacuum for 12 h to afford IVbas a white solid (51.8 g; 73% mol yield from XI). Mp. (withdecomposition) 37° C. ¹H NMR (CDCl₃, 400 MHz) δ 9.4 (bs, 3h), 7.8-7.4(m, 8H), 6.2 (dd, 1H), 5.2 (m. 2h), 4.6 (q, 1H), 4.1 (d, 1h), 3.8 (s,1H), 1.5 (d, 3h).

Example 3

Step 1 Preparation of(3R,6S)-3-tert-Butyldihydro-1H-pyrrolo[1,2-c][1,3]oxazole-1,5(6H)-dione

Method (a):

To a 250 mL three neck flask equipped with an agitator, thermometer,Dean Stark, reflux condenser, and a nitrogen inlet, were addedL-pyroglutamic acid (20.0 g, 154.8 mmol), toluene (60 mL), diethyleneglycol dimethyl ether (60 mL), trimethylacetaldehyde (40.0 g, 464.4mmol), and CH₃SO₃H (1.5 g, 15.6 mmol). The reaction mixture was heatedto reflux at 102-120° C. (reflux) for 14.5 h or until reactioncompletion with water removal via a Dean-Stark apparatus. The reactionmixture was cooled to 35° C. and distilled under vacuum to a finalvolume of 50 mL.

The mixture was cooled to 20° C. over 1 h, and n-heptane (140 mL) wasadded over 1 h. The reaction mixture was cooled to −5° C. over 1 h andagitated for 1 h. The slurry was filtered and washed with heptane (60mL) and water (60 mL), dried under vacuum at 50° C. to afford XIV (23.9g, 79% yield) as an off-white crystalline solid. Mp (with decomposition)116-168° C., ¹H-NMR (DMSO-d₆) δ 5.32 (s, 1H), 4.53 (t, J=8.1 Hz, 1H),2.69 (m, 1H), 2.43 (m, 1H), 2.30 (m, 1H), 2.29 (m, 1H), 0.91 (s, 9H).LC/MS calculated for C₁₀H₁₆NO₃ (M+H)⁺ (m/z): 197.231; found: 197.227.

Method (b):

To a 250 mL three neck flask equipped with an agitator, thermometer,reflux condenser, and a nitrogen inlet, was added L-pyroglutamic acid(200 g, 1.6 mol), NMP (400 mL), trimethylacetaldehyde (500 mL, 397 g,4.6 mol), and CH₃SO₃H (30 mL 44.5 g, 0.46 mol). The reaction mixture washeated to 82.5° C. (reflux) for 15 min and TFAA (240 mL, 1.1 eq.) wasadded slowly over a period of 4.5 h. The temperature was maintained at82.5° C. for an additional 4.5 h. The flask was cooled to 20° C. over 1h and the mixture was transfer to a slurry of NaHCO₃ (325 g, 3.9 mmol)in water (2 L) at 5° C. over 1 h. The slurry was filtered and washedwith ice-cold water (400 mL). The wet cake was then dried under vacuumat 50° C. to afford XIV (244 g, 72% yield) as an off-white crystallinesolid.

Method (c):

To a 250 mL three neck flask equipped with an agitator, thermometer,reflux condenser, and a nitrogen inlet, was added L-pyroglutamic acid(250 g, 1.94 mol), toluene (1000 mL), and (CH₃)₃SiNHSi(CH₃)₃ (890 mL,4.26 mol). The mixture was heated to reflux for 6 h, during which timethe reflux temperature slowly increased from 80 to 100° C. After 6 h,the mixture was distilled to a volume of 400 mL at 80 mm Hg and 50° C.Additional toluene (1000 mL) was charged and the mixture was distilledto a volume of 400 mL in vacuum. Then trimethylacetaldehyde (500 mL, 397g, 4.6 mol), and CH₃SO₃H (30 mL 44.5 g, 0.46 mol) were charged and thereaction mixture was heated to 90° C. for 4 h. The reaction mixture wascooled to 35° C., toluene (1200 mL) was added and the mixture wasdistilled under vacuum to a final volume of 1000 mL. The flask wascooled to 20° C. and the mixture was transferred to a solution of NaHCO₃(65 g) in water (1250 L) at −5° C. over 1 h. The slurry was filtered andwashed with ice-cold water (400 mL) and then ice-cold isopropyl alcohol(100 mL). The wet cake was then dried under vacuum at 50° C. to affordthe compound of Formula XIV (267 g, 68% yield) as an off-whitecrystalline solid.

Method (d):

To a 1 L three neck flask equipped with an agitator, thermometer, refluxcondenser and a nitrogen inlet, was charged L-pyroglutamic acid (50 g,0.39 mol), toluene (450 mL) and Et₃N (113 mL 0.81 mol). (CH₃)₃SiCl (103mL, 0.81 mol) was added while keeping the temperature below 30° C. Thereaction mixture was heated to 110° C. and agitated for a period of 3 h.The suspension was cooled to 5° C. and diluted with heptane (100 mL).The triethylammonium hydrochloride salt was removed by filtration andwashed with a toluene/heptane solution (200 mL). The filtrate wasconcentrated to a final volume of 150 mL and NMP (50 mL),trimethylacetaldehyde (100 mL, 0.78 mol) and CH₃SO₃H (2.5 mL, 0.04 mol)was added. The reaction mixture was heated to 80° C. for 24 h thencooled to 40° C. The reaction mixture was concentrated to about 100 mLand diluted with acetone (100 mL). The reaction mixture was transferredto a solution of NaHCO₃ (13 g) in water (250 mL) at 20° C. Thesuspension was cooled to 5° C. and stirred for 1 h. The slurry wasfiltered and washed with ice-cold water (50 mL) and then ice-coldisopropyl alcohol (50 mL). The product was then dried under vacuum at45° C. to afford XIV (48.3 g, 63%) as an off-white crystalline solid.

Method (e):

To a 1 L three neck flask equipped with an agitator, thermometer, refluxcondenser and a nitrogen inlet, was charged L-pyroglutamic acid (20 g,0.16 mol), trimethylacetaldehyde (50 mL, 0.39 mol), methane sulfonicacid (1.4 ml, 0.02 mol) toluene (140 mL) and N-methylpyrrolidone (20mL). The mixture was heated to 90° C. and maintained at 90° C. whilstslowly adding trifluoroacetic anhydride (27 mL). The reaction wasmaintained at 90° C. for 8 hours, achieving 100% conversion of the acid.

Step 2

To a 2 L three neck flask equipped with an agitator, thermometer, refluxcondenser, and a nitrogen inlet were charged XIV (100 g, 0.5 mol), CuCl(10 g), DMI (100 mL), THF (1.2 L), and methyl formate (100 mL). Aftercooling to below [−60]° C., LHMDS (700 mL, 1.0 M in THF) was charged ata rate such that the temperature did not exceed −60° C. After additionof LHMDS, TMSCl was charged at a rate such that the temperature did notexceed [−60]° C. The mixture was warmed to between 0 and 10° C. over 30min and the batch was concentrated in vacuum to 250 mL and EtOAc (300mL) was added. To a mixture of citric acid (120 g), water (1 L), andEtOAc (1 L) at 5° C. was then transferred the crude reaction mixtureover 30 min while maintaining a temperature between 0 and 15° C. Theflask containing the crude mixture was then rinsed with EtOAc (200 mL).After agitating for 10 min, the layers were separated and the organiclayer was sequentially washed with 12.5% aq. citric acid (800 mL), 10%aq. citric acid (700 mL) and 8% aq. citric acid solution (600 mL). To amixture of the organic layer and water (300 mL) at 5° C., was chargedtrifluoroacetic acid (30 mL) over 10 min while maintaining a temperaturebetween 5 and 15° C. After completing the addition, the mixture waswarmed to 25° C. and agitated for 3.5 h. An aqueous solution of KHCO₃(200 mL, 20%) was charged over 30 min while maintaining a temperaturebelow 20° C., followed by saturated NaCl solution (500 mL) and thelayers were separated and split. The aqueous layer was back extractedwith EtOAc (250 mL). The EtOAc fraction was washed with saturated NaClsolution (500 mL). Water (35 mL) was charged to the combined organiclayers and the solution was concentrated in vacuum to a final volume of100 mL. MTBE (400 mL) was charged and the mixture was concentrated invacuum to a final volume of 100 mL. Additional MTBE (400 mL) was chargedand the suspension was agitated for 2 h at RT. The resulting slurry wasfiltered, rinsed with MTBE (200 mL) and XV was obtained in 61% yield (70g) after drying in vacuum at 45° C. for 12 h. MP 196° C.-198° C. ¹H NMR(400 MHz in CDCl₃): δ 9.7 (s, 1H), 5.5 (s, 1H), 2.7 (m, 1H), 2.6 (m,1H), 2.4 (m, 2H), 0.9 (s, 9H). ¹³CNMR (400 MHz, CDCl₃):

192.0, 181.1, 169.7, 97.6, 73.4, 36.5, 31.7, 30.6, 24.6. ES-MS: [M+H⁺]calcd for C₁₁H₁₅NO₄: 226.10; found: 226.27.

Step 3

To a 3-neck 1-L flask equipped with a thermometer and mechanical stirrerwere charged Ph₃PCH₃Br (122.9 g; 344.1 mmol) and toluene (100 mL). At10° C., a solution of NaHMDS in toluene (540 mL, 13%) was added slowlyto maintain the temperature at 10° C. This slurry was agitated at 10° C.for 1 h and then added slowly to a slurry of XV (50 g, 222 mmol) intoluene (100 mL) at 10° C., over a period of 2-4 h via peristaltic pump.After stirring for an additional hour, the batch was quenched into asolution of NaCl (10% aqueous), AcOH (38.5 mL, 666 mmol), and toluene(50 mL) over 30 min at 25° C. The resulting mixture was stirred for 30min and the layers were settled, split and the lower aqueous layer wasremoved. The organic layer was then treated with MgCl₂ powder (70 g, 776mmol) for 2 h at RT. The solids were then filtered off and the solidMgCl₂-triphenylphosphin oxide complex was washed with MTBE (100 mL). Theorganic filtrates were combined, washed with aq. NaCl (100 mL, 10%) andconcentrated to 100 mL in vacuum. To the resulting slurry was chargedheptane (400 mL) and the volume was reduced to 100 mL in vacuum.Additional heptane (400 mL) was added and the volume was reduced to 250mL in vacuum. A third portion of heptane (400 mL) was added; the batchwas then cooled to 0° C. over 2 h and stirred for another 2 h at thistemperature. The solids were then removed by filtration and washed withice-cold N-heptane (200 mL). The wet cake was dried under vacuum at 30°C. for 18 h to produce 62 g of XVI (63% yield) as an off-white solid. Mp85° C.-87° C. ¹H-NMR (CDCl₃) δ 5.98 (m, 1H), 5.31 (m, 3H), 2.56 (m, 1H),2.17 (m, 3H), 0.81 (s, 9H). ES-MS: [M+H⁺] calcd for C₁₂H₁₅NO₃: 224.12;found: 224.38.

Step 4

To a 500 mL three-necked flask (1) equipped with an agitator,thermometer, and a nitrogen inlet were added XVI (30.0 g, 132 mmol) andTHF (300 mL). After cooling mixture to −20° C., lithiumtri(t-butoxy)aluminum hydride (1 M THF; 162 mL) was added over 2 h whilemaintaining the temperature around −20° C. Temperature was then raisedto 0° C. over 12 h. The reaction is quenched with the addition of EtOAc(12.0 mL) over 30 min, followed by agitation for 30 min at 0° C., andthen slow addition of glacial AcOH (12.0 mL) over 30 min. To another 1-Lthree-necked flask (2) equipped with an agitator, thermometer, and anitrogen inlet were added finely ground sodium sulfate decahydrate (30g, 93 mol) and THF (150 mL) at 0° C. The reaction mixture in flask (1)was slowly transferred to flask (2) containing the sodium sulfatedecahydrate solution while maintaining the temperature at 0° C. Thetemperature of flask (2) was raised over a 1 h period and agitated for 1h at 20° C. The contents of flask (2) were filtered, the wet cake waswashed three times with THF (180 mL, 120 mL, and then 120 mL), and thefiltrates were combined and concentrated in vacuum to 60 mL. To a 1000mL three-necked flask (3) equipped with an agitator, thermometer, and anitrogen inlet was added water (300 mL). The mixture from flask (2) wascooled to 5° C. and then added to the water with high agitation over a 2h period, whereupon the product precipitated. The slurry wasconcentrated in vacuum to 450 mL and the solid was isolated viafiltration. The wet cake was dried at 50° C. for 12 h to afford 25.1 gof the compound of formula H as a white/off white solid in 83% yield. Mp88° C. ¹H-NMR 500 MHz (DMSO-d₆) δ 6.92 (d, J=3.9 Hz, 1H), 6.03 (dd,J=15.8, 11.1 Hz, 1H), 5.36 (d, J=3.9 Hz, 1H), 5.24 (d, J=17.6 Hz, 1H),5.11 (d, J=11.1 Hz, 1H), 4.75 (s, 1H), 2.72 (ddd, J=16.8, 10.2, 8.7 Hz,1H), 2.28 (ddd, J=16.7, 10.5, 3.7 Hz, 1H), 2.45 (ddd, J=12.8, 10.4, 8.9Hz, 1H), 1.82 (ddd, J=12.9, 10.5, 3.7 Hz, 1H), 0.85 (s, 9H). ¹³C-NMR(125 MHz DMSO-d₆) δ 180.7, 142.1, 113.3, 96.2, 93.9, 73.6, 34.5, 33.2,26.8, 25.9 ppm. LC/MS calculated mass for C₁₂H₂₀NO₃ [M+H]+ (m/z)226.14377, found 226.14398.

Example 4

5(R)-[[[I(S)-[[I(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-I-phenyl-2-propenyl]amino]methyl]-5-ethenyl-2-pyrrolidinone4-methylbenzenesulfonate hydrate

a) To a mixture of II (49.6 g, 0.22 mol) in EtOH (50 mL) and Et₃N (50mL) was added water (50 mL) at RT. The resulting mixture was agitated at25° C. After 4 h, more EtOH (350 mL) was added and the mixture wasconcentrated in vacuum to 180 mL.b) To a mixture of IVa (100 g, 0.193 mol) in toluene (440 mL) was addedat RT aq. NaOH (440 mL, 1N). The reaction mixture was agitated at RT for30 min. The aqueous layer was separated and the organic layer was washedtwice with 10% NaCl aqueous solution (440 mL). The crude product IVfreebase was used without further purification.

The crude solution of III in EtOH was then added to the above solutionof IV free base in toluene and the resulting mixture was heated toreflux. Water was removed from reaction through azeotropic distillationand more toluene/EtOH (3/2 v/v) were added if necessary based onconversion. After reaction completion, EtOH was removed throughsolvent-exchange with toluene and the crude solution of V in toluene(530 mL) was slowly added to a mixture of NaBH(OAc)₃ (57.3 g, 0.27 mol)and AcOH (15.5 mL, 0.27 mol) in toluene (270 mL) at RT. The reactionmixture was agitated at RT for about 6 h, and then water (440 mL) wasslowly added and the resulting mixture was agitated at RT for 1 h. Theaqueous layer was separated and the organic layer was washed once with5% NaHCO₃ aqueous solution (440 mL) and twice with 10% NaCl aqueoussolution (440 mL) to obtain a solution of VI. Solvent was exchanged toisopropanol through vacuum distillation.

c) To the crude free base solution of VI in isopropanol (200 mL) wasadded at RT a solution of p-toluenesulfonic acid (40.4 g, 0.212 mol) inisopropanol (270 mL) followed by water (440 mL). The mixture was seededwith approximately 0.5 g of crystalline VIa and agitated at RT for 1 hbefore addition of more water (880 mL). After agitation for 8 h at RT,the crystals were collected by filtration, washed withisopropanol/water, water and heptanes, and dried to give VIa as a whitecrystalline powder (122 g, yield 88% based on V). Mp 80.2-93.4° C. ¹HNMR (CDCl₃, 400 MHz) δ 9.52 (bs, 1H), 8.80 (bs, 1H), 8.33 (s, 1H), 7.74(d, J=8.1 Hz, 2H), 7.73 (s, 1H), 7.55 (s, 2H), 7.52-7.50 (m, 2H),7.37-7.29 (m, 3H), 7.16 (d, J=8.0 Hz, 2H), 6.22 (dd, J=17.5, 11.1 Hz,1H), 5.90 (dd, J=17.2, 10.6 Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 5.34 (d,J=17.1 Hz, 1H), 5.25 (d, J=17.5 Hz, 1H), 5.23 (d, J=10.6 Hz, 1H), 4.79(q, J=6.3 Hz, 1H), 4.35 (d, J=10.5 Hz, 1H), 3.83 (d, J=10.4 Hz, 1H),3.35-3.18 (m, 2H), 2.35 (s, 3H), 2.35-2.15 (m, 3H), 2.00-1.91 (m, 1H),1.39 (d, J=6.4 Hz, 3H).

Example 5

(5R,8S)-8-[1-(R)-(3,5-Bis-trifluoromethyl-phenyl)-ethoxymethyl]-8-phenyl-1,7-diaza-spiro[4.5]dec-9-en-2-one,hydrochloride

A solution of 130.0 g (181.4 mmol) of VIa (VI p-toluenesulfonic acid(TsOH) monohydrate) and 51.7 g (272.1 mmol) of toluenesulfonic acid intoluene (3.25 L) was distilled under reduced pressure (60-80 mm Hg) at50° C. to a final volume of 1.95 L. Upon completion of the distillation,the toluene solution containing VIa and toluenesulfonic acid wasevacuated to ˜80 mm Hg and then purged with N₂ via a submersed needle.This sparging process was repeated two times. In a second reactor, 1.14g (1.8 mmol) of Hoveyda-Grubbs' Second Generation Catalyst (HG-II),having the structure

was dissolved in anhydrous, degassed toluene (650 mL, prepared in amanner identical to the above toluene solution). This catalyst solutionwas slowly charged to the first reactor over 30 min at between 60 to 80°C. The reaction mixture was stirred at the same temperature range for 4h and the conversion is monitored by HPLC. Upon completion of thereaction, a 16% solution of aq. Na₂S₂O₅ (650 mL) was added to thereactor over 30 min and stirred at 60 to 80° C. for 3 h, after which themixture was cooled to 25° C. and an aq. 0.5 N NaHCO₃ solution was added(650 mL). The biphasic mixture was then stirred at 25° C. for 1 h,allowed to settle and the lower aqueous layers and interface wereremoved. The organic phase was washed with 0.5 N aq. NaHCO₃ (1.3 L),then 10% aq. NaCl (1.3 L) and finally water (1.3 L). The organic phasewas filtered through a pad of celite and to the filtrate was charged 12N aq. HCl (14.4 mL). The toluene/H₂O was concentrated to below 390 mLunder vacuum (50-60 mm Hg) at a temperature above 50° C. The resultingsolution was cooled to 45° C. and seeded with Vila in heptanes (65 mL).After 30 min of stirring at 45° C., the reaction mixture was cooled from45° C. to 20° C. over 6 h. Then heptanes (1.82 L) were charged to thereaction mixture at 20° C. over 3 h. The solid precipitate was filteredand washed with heptanes (520 mL). The wet cake was dried at 25° C. for4 h then 65° C. in a vacuum oven overnight to afford 83 g of VIIa (85%yield) as a grayish-to of-white colored solid. In addition, the aqueouslayers can be combined and filtered to recover the Ru-salts. Mp 190-195°C. ¹H NMR (400 MHz, CDCl₃) δ 10.58 (bs, 1H), 10.21 (bs, 1H), 8.25 (s,1H), 7.70 (s, 1H), 7.58-7.43 (m, 7H), 6.16 (d, J=11, 1H), 6.05 (d, J=11,1H), 4.65 (q, J=6 Hz, 1H), 4.23 (d, J=9.4 Hz, 1H), 3.81 (d, J=13.6 Hz,1H), 3.73 (d, J=9.5 Hz, 1H), 2.99 (app. t, J=11 Hz, 1H), 2.48-2.40 (m,2H), 2.06-1.94 (m, 2H), 1.43 (d, J=6.4 Hz, 1H); ¹³C NMR (100.6 MHz,CDCl₃) δ 176.7, 145.8, 135.1, 132.5, 132.4, 132.0, 130.0, 129.7, 127.5,127.0, 126.5, 124.8, 122.1, 122.0, 122.0, 78.4, 73.1, 63.5, 55.9, 50.0,32.2, 29.6, 24.3 ppm. ES-MS: [M+H⁺] calcd for C₂₅H₂₅F₆N₂O₂: 499.18;found: 499.05.

Example 5a—Reduction of Metathesis Catalyst in the Presence of a PTC

Example 5 was repeated as described above until HPLC indicated completeconversion of the compound of Formula VIa to the compound of FormulaVila. Upon completion of the reaction, a 16% solution of aq. Na₂S₂O₅(650 mL) was added to the reactor over 30 min along with 2.5 g oftetra-n-butyl-ammonium chloride. The mixture was stirred for 0.7 hoursmaintaining the reaction mixture at a temperature between 60° C. and 80°C., after which the mixture was cooled to 25° C. and an aq. 0.5 N NaHCO₃solution was added (650 mL). The biphasic mixture was then stirred at25° C. for 1 h, allowed to settle and the lower aqueous layers andinterface were removed, and the reaction mixture worked up as describedin Example 5. The results were the same, demonstrating the advantageprovided by the use of a PTC in reducing the metathesis catalyst via theprocess of Scheme 4 described herein above.

Example 6

(5S,8S)-8-[1-(R)-(3,5-Bis-trifluoromethyl-phenyl)-ethoxymethyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-onehydrochloride hydrate

To a mixture of Vila (100 g, 0.187 mol) in toluene (600 mL) was chargedaqueous NaOH (5%, 300 mL). After agitating the mixture for 15 min, theorganic layer was separated and washed with brine (10%, 2×500 mL). Theorganic layer was then subjected to hydrogenation with Pd/C (10 g, 10%in carbon 50% wet) and Nuchar-Aquaquard (50 g) under 60 to 80 psipressure for 4 to 8 h or until reaction completion. The reaction wasfiltered through a pad of celite. The celite was washed with toluene(100 mL). The combined toluene solution was concentrated to 500 mL. Asolution of aqueous HCl (˜35%, 20 ml, ˜1.3 eq) was slowly added into thereaction solution and the mixture was slowly cooled down to 0° C. Theproduct was collected by filtration and washed with a solution oftoluene and MTBE (1:1). The wet cake was dried at 40 to 45° C. to give95 g of VIII (95% yield) as a white to off-white solid. Mp152-154° C. ¹HNMR (400 MHz in DMSO-d₆): δ 10.62 (dd, J=10, 12 Hz, 1H, N—H), 9.62 (d,J=12 Hz, 1H, N—H), 7.92 (br, NH), 7.92 (s, 2H), 7.66 (s, 1H), 7.58 (d,J=7.5 Hz, 2H), 7.44 (m, 2H), 7.40 (m, 1H), 4.65 (q, J=6.4 Hz, 1H), 4.30(d, J=10 Hz, 1H), 3.36 (d, J=10 Hz, 1H), 3.22 (d, J=13 Hz, 1H), 2.88(dd, J=13, 10 Hz, 1H), 2.49 (md, J=14.5 Hz, 1H), 2.19 (md, J=14.5 Hz,1H), 2.15 (m, 1H), 2.24 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H), 1.41 (d,J=6.4 Hz, 3H), 1.79 (md, J=13.5 Hz, 1H), 1.39 (md, J=13.5 Hz, 1H); ¹³CNMR (100 MHz, DMSO): δ 175.3, 146.6, 134.7, 130.1 (2) (²J_(CF)=33 Hz),128.5 (2), 128.0, 126.4 (2), 126.3 (2) (³J_(CF)=2.6 Hz), 120.9(³J_(CF)=3.7 Hz), 119.9 (2) (J_(CF)=273 Hz), 75.8, 73.2, 63.1, 55.6,48.9, 31.2, 30.8, 28.8, 24.8, 23.1.

Example 7

(5S,8S)-8-(1-(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-onehydrochloride monohydrate

Method 1:

VIII (20 g) was suspended in 155.0 g of an EtOH-isopropanol-water-HClstock solution (stock solution preparation: 168.6 g absolute EtOH, 368.7g water, 11.6 g of isopropanol, 1.6 g of 37% HCl) and heated to reflux(78-79° C.) until a clear solution was obtained. The mixture was thencooled slowly to a temperature between 72 and 73° C. and optionally,seeded with 0.4 g of micronized Ia suspended in 20 ml of the stocksolution. The amount of seed used can be varied between 0.0 and 2.0 g toeffect changes in the particle size distribution (PSD) of the product.The batch was further cooled to 0° C. at a rate of 0.5° C./min, filteredunder vacuum and washed with 40 mL of stock solution. Finally, the batchwas dried under vacuum at a temperature of 40° C. for at least 18 h togive 18.7 g (91.2%) of Ia as white solid.

Method 2:

Thirty grams of VIII was suspended in 231-232 g of a 40:60% by volumeEtOH-water stock solution (stock solution preparation: 400 mL EtOH (95%EtOH, 5% MeOH), 600 mL water,) and heated to reflux (78-79° C.) until aclear solution was obtained. The mixture was then cooled slowly to atemperature between 67.5 and 68.5° C. and seeded with 1.5 g ofmicronized Ia suspended in 30 mL of the stock solution. The amount ofseed used can be varied between 0.0 and 3.0 g to effect changes in thePSD of the product. The batch was further cooled to 0° C. at a rate of0.5° C./min and an additional 35 g of water was added to improve yield.The batch was filtered under vacuum and washed with 60 mL of a 35:65 byvolume EtOH:water solution. Finally, the batch was dried under vacuum ata temperature of 40° C. for at least 18 h to produce 28.2-28.9 g(89.6-91.8%) of Ia.

Method 3:

VIII (11.6 g) was dissolved at RT in EtOH (47 mL). To the solution,water (186 mL) was added over about 35 min and the temperature of thesuspension was maintained at 25° C. The resulting suspension was cooledto 0° C. to improve yield and agitated for 30 min. The batch was thenfiltered under vacuum and washed with 25 mL of a 20:80 by volumeEtOH:water solution. Finally, the batch was dried under vacuum at atemperature of 40° C. for at least 18 h. Yield: 9.7 g (83.6%).

Method 4:

VIII (22.9 g) was dissolved at RT in EtOH (76 mL). The solution was thenfiltered and added over about 25 min to water (366.8 g). The resultingsuspension was cooled to 0° C. to improve yield and agitated for 30 min.The batch was then filtered under vacuum and washed with 70 mL of a20:80 by volume EtOH:water solution. Finally, the batch was dried undervacuum at a temperature of 40° C. for at least 18 h. Yield: 20.4 g(89.1%).

Method 5:

VIII (16.4 g) was suspended at 25° C. in toluene (115 mL). 50 mL of a 1NNaOH solution was added to the suspension and the batch was agitated for30-60 min. The batch was then allowed to split for about 30 min and theaqueous bottom layer was removed. To the organic layer, 2.82 g of 37%HCl was added to form and precipitate Ia, the monohydrate hydrochloridesalt. The batch was stirred for 30 min and then filtered under vacuumand washed with toluene (32 mL). Finally, the batch was dried undervacuum at a temperature of 40° C. for at least 18 h to afford 12.4 g(75.6%) of Ia.

Using similar procedures, isomers Ib to Ih were prepared. The physicaldata for the compounds is as follows:

Formula Ib (S,R,R):

Isolated as a pale brown oil after column chromatography. ¹H NMR (400MHz in DMSO-d₆): δ 10.23 (dd, J=10, 12 Hz, 1H, N—H), 9.68 (d, J=12 Hz,1H, N—H), 7.93 (s, 1H), 7.75 (s, 2H), 7.61 (d, J=7.5 Hz, 2H), 7.42 (m,2H), 7.35 (m, 1H), 4.53 (q, J=6.4 Hz, 1H), 3.82 (d, J=10 Hz, 1H), 3.67(d, J=10 Hz, 1H), 3.00 (d, J=13 Hz, 1H), 2.65 (dd, J=13, 10 Hz, 1H),2.46 (md, 2H), 2.15 (m, 1H), 2.24 (m, 1H), 1.81 (m, 1H), 1.14 (d, J=6.4Hz, 3H), 1.53 (md, J=13.5 Hz, 1H), 1.62 (md, J=13.5 Hz, 1H); ¹³C NMR(100 Mhz, DMSO): δ 175.9, 147.1, 134.9, 130.4 (2) (²J_(CF)=33 Hz), 130.0(2), 128.5, 127.0 (2), 125.0 (2) (³J_(CF)=2.6 Hz), 122.3 (³J_(CF)=3.7Hz), 121.3 (2) (J_(CF)=273 Hz), 76.5, 73.7, 62.9, 56.0, 47.5, 31.1,30.9, 29.4, 25.6, 22.8. MS. Calculated for C₂₅H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺500.47 (m/z): 500.19.

Formula Ic (R,S,R):

Isolated as an off-white solid from diethyl ether. ¹H NMR (400 MHz inDMSO-d₆): δ 7.95 (d, J=12 Hz, 1H, N—H), 7.79 (d, J=7.5 Hz, 2H), 7.52(md, 2H), 7.43 (d, J=7.5 Hz, 1H), 7.32 (m, 2H), 7.21 (m, 1H), 4.55 (q,J=6.4 Hz, 1H), 3.28 (d, J=10 Hz, 1H), 3.11 (d, J=10 Hz, 1H), 2.50 (d,J=13 Hz, 1H), 2.40 (d, J=13, 1H), 2.22 (md, 2H), 2.18 (m, 2H), 1.76 (m,2H), 1.30 (d, J=6.4 Hz, 3H), 1.45 (md, J=13.5 Hz, 2H); ¹³C NMR (100 Mhz,DMSO): δ 175.9, 147.9, 142.2, 130.6 (2) (²J_(CF)=33 Hz), 129.8 (2),128.4, 127.5 (2), 126.6 (2) (³J_(CF)=2.6 Hz), 125.0, 122.3, 121.2 (2),78.4, 76.4, 58.4, 57.4, 50.4, 33.3, 29.8, 27.9, 23.6. MS. Calculated forC₂₆H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺ 500.47 (m/z): 500.18.

Formula Id (R,R,R):

Isolated after purification by column chromatography, via trituration in1:2 diethyl ether/heptane as an off white solid. ¹H NMR (400 MHz inDMSO-d₆): δ 9.71 (dd, J=10, 12 Hz, 1H, N—H), 8.92 (d, J=12 Hz, 1H, N—H),8.51 (br, NH), 7.99 (s, 1H), 7.88 (s, 2H), 7.66 (d, J=7.5 Hz, 2H), 7.52(m, 2H), 7.48 (m, 1H), 4.61 (q, J=6.4 Hz, 1H), 4.03 (d, J=10 Hz, 1H),3.78 (d, J=10 Hz, 1H), 3.22 (d, J=13 Hz, 1H), 2.88 (m, J=13, 10 Hz, 1H),2.49 (md, J=14.5 Hz, 1H), 2.19 (md, J=14.5 Hz, 1H), 2.25 (m, 3H), 1.90(m, 2H), 1.87 (md, 1H), 1.72 (md, J=13.5 Hz, 1H), 1.28 (d, J=6.5 Hz,3H); ¹³C NMR (100 Mhz, DMSO-d₆): δ 173.6, 147.0, 135.4, 130.2 (2)(²J_(CF)=33 Hz), 129.0, 128.6, 127.8 (2), 127.0, 126.3 (2) (³J_(CF)=2.6Hz), 120.9, 122.3, 121.4, 119.6, 76.6, 73.3, 63.4, 52.9, 49.1, 31.5,29.2, 24.9, 22.6. MS. Calculated for C₂₆H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺500.47(m/z): 500.34.

Formula Ie (S,S,S)

Isolated as a fine white HCl salt by triturating in diethyl ether at 10°C. for 3 hours after column chromatography. ¹H NMR (400 MHz in DMSO-d₆):δ 10.58 (dd, J=10, 12 Hz, H, N—H), 76 (d, J=12 Hz, 1H, N—H), 8.57 (s,1H), 8.11 (s, 1H), 7.89 (d, J=12 Hz, 2H), 7.61 (d, J=10 Hz, 2H), 7.55(m, 3H), 4.66 (q, J=6.4 Hz, 1H), 4.09 (d, J=10 Hz, 1H), 3.83 (d, J=10Hz, 1H), 3.27 (d, J=13 Hz, 1H), 2.65 (dd, J=13, 10 Hz, 1H), 2.35 (md,2H), 2.29 (m, 1H), 1.97 (m, 1H), 1.32 (d, J=6.4 Hz, 3H), 1.58 (dd,J=13.5 Hz, 9 Hz, 1H), 1.78 (md, J=13.5 Hz, 1H); ¹³C NMR (100 MHz,DMSO-d₆): δ 175.7, 147.0, 134.9, 130.4 (2) (²J_(CF)=33 Hz), 130.0 (2),128.5, 127.0 (2), 126.9 (2) (³J_(CF)=2.6 Hz), 122.3 (³J_(CF)=3.7 Hz),121.4 (2) (J_(CF)=273 Hz), 76.6, 73.7, 63.1, 56.0, 47.8, 31.6, 31.1,29.2, 25.9, 22.9. MS. Calculated for C₂₆H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺ 500.47(m/z): 500.4.

Formula If (S,R,S):

After purification by column chromatography, isolated as an off-whiteHCl salt from diethyl ether. ¹H NMR (400 MHz in DMSO-d₆): δ 10.30 (dd,J=10, 12 Hz, 1H, N—H), 9.81 (d, J=12 Hz, 1H, N—H), 8.11 (s, 1H), 7.86(s, 1H), 7.58 (m, 4H), 7.46 (m, 4H), 4.84 (q, J=6.4 Hz, 1H), 4.28 (d,J=13 Hz, 1H), 3.59 (s, 1H), 3.52 (d, J=10 Hz, 1H), 3.36 (d, J=10 Hz,1H), 3.01 (d, J=13 Hz, 1H), 2.72 (dd, J=13, 10 Hz, 1H), 2.43 (md, 2H),2.08 (m, 2H), 1.57 (d, J=6.4 Hz, 3H), 1.85 (md, J=13.5 Hz, 1H), 1.72(md, J=13.5 Hz, 1H); ¹³C NMR (100 Mhz, DMSO-d₆): δ 175.7, 147.1, 134.6,130.7 (2) (²J_(CF)=33 Hz), 130.3 (2), 128.9, 128.4 (2), 126.8 (2)(³J_(CF)=2.6 Hz), 122.3 (³J_(CF)=3.7 Hz), 121.3 (2) (J_(CF)=273 Hz),76.2, 73.7, 66.9, 49.3, 43.8, 31.1, 31.6, 29.2, 25.2, 23.5. MS.Calculated for C₂₅H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺ 500.47 (m/z): 500.3.

Formula Ig (R,S,S)

Isolated as an off-white HCl salt triturated in diethyl ether at 5° C.for 12 hours after purification by column chromatography. ¹H NMR (400MHz in DMSO-d₆): δ 10.00 (dd, J=10, 12 Hz, 1H, N—H), 9.64 (d, J=12 Hz,1H, N—H), 7.94 (s, 1H), 7.78 (s, 2H), 7.63 (d, J=7.5 Hz, 2H), 7.41 (m,2H), 7.37 (m, 1H), 4.55 (q, J=6.4 Hz, 1H), 3.82 (d, J=10 Hz, 1H), 3.69(d, J=10 Hz, 1H), 3.10 (d, J=13 Hz, 1H), 2.76 (dd, J=13, 10 Hz, 1H),2.20 (md, 2H), 2.15 (m, 1H), 1.94 (m, 1H), 1.83 (m, 1H), 1.14 (d, J=6.4Hz, 3H), 2.44 (md, J=13.5 Hz, 2H); ¹³C NMR (100 Mhz, DMSO-d₆): δ 175.8,147.1, 134.9, 130.2 (2) (²J_(CF)=33 Hz), 129.0 (2), 127.8, 127.0 (2),125.0 (2) (³J_(CF)=2.6 Hz), 122.3 (³J_(CF)=3.7 Hz), 121.3 (2)(J_(CF)=273 Hz), 76.5, 73.7, 62.9, 56.0, 47.5, 31.1, 30.9, 29.4, 25.7,22.8. MS. Calculated for C₂₅H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺ 500.47 (m/z):500.33.

Formula Ih (R,R,S):

Isolated as the HCl salt by trituration in diethyl ether at 5° C. for 3hours after purification by column chromatography. ¹H NMR (400 MHz inDMSO-d₆): δ 9.56 (dd, J=10, 12 Hz, 1H, N—H), 9.42 (d, J=12 Hz, 1H, N—H),7.97 (s, 1H), 7.97 (s, 1H), 7.52 (s, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.41(m, 2H), 7.35 (m, 1H), 4.60 (q, J=6.4 Hz, 1H), 4.20 (d, J=10 Hz, 1H),3.59 (s, J=10 Hz, 1H), 3.16 (d, J=13 Hz, 1H), 2.87 (dd, J=13, 10 Hz,1H), 2.19 (md, 2H), 2.12 (m, 1H), 1.94 (m, 1H), 1.72 (m, 1H), 1.36 (d,J=6.4 Hz, 3H), 1.63 (md, J=13.5 Hz, 1H), ¹³C NMR (100 Mhz, DMSO-d₆): δ175.8, 147.1, 131.2, 130.4 (2) (²J_(CF)=33 Hz), 130.1 (2), 128.5, 126.7(2), 124.9 (2) (³J_(CF)=2.6 Hz), 122.2 (³J_(CF)=3.7 Hz), 121.3 (2)(J_(CF)=273 Hz), 119.5, 76.3, 73.7, 66.1, 56.1, 47.6, 31.1, 30.9, 26.1,23.8. MS. Calculated for C₂₅H₂₆F₆N₂O₂.HCl.H₂O, (M+H)⁺ 500.47 (m/z):500.3.

The above description of the invention is intended to be illustrativeand not limiting. Various changes or modifications in the embodimentsdescribed herein may occur to those skilled in the art. These changescan be made without departing from the scope or spirit of the invention.

What is claimed is:
 1. A process for preparing compound VIII:

the process comprising treating compound I:

with hydrochloric acid; wherein compound I is prepared from compound VIIor VIIb:

wherein “salt 3” represents at least one proton bonded to a basefunctional group in the compound VII.
 2. The process of claim 1, whereinthe compound I is prepared by treating compound VII:

with a reagent suitable to reduce compound VII, wherein “salt 3”represents at least one proton bonded to a base functional group in thecompound VII.
 3. The process of claim 1, wherein the compound I isprepared by treating compound VIIb

with a reagent suitable to reduce compound VIIb.
 4. The process of claim3, wherein the compound VIIb is prepared by treating compound VII:

with a hydroxide base of Formula M-OH, wherein “salt 3” represents atleast one proton bonded to a base functional group in the compound VII;and “M” is an alkaline metal or alkali earth metal to provide thecompound VIIb.
 5. The process of claim 2 or claim 4, wherein thecompound VII is prepared by treating compound VIa:

with a ring-closing metathesis catalyst, wherein “salt 2” represents atleast one proton bonded to a base functional group in the compound VIa.6. The process of claim 5, wherein the compound VIa is prepared bytreating compound VI:

with an acid.
 7. The process of claim 6, wherein the compound VI isprepared by treating compound V:

with a reagent suitable to reduce compound V.
 8. The process of claim 7,wherein compound V is prepared by combining compounds III and IV to forma mixture:

wherein the mixture is heated.
 9. The process of claim 1, wherein thecompound VIII is recrystallized to provide compound Ia:


10. The process of claim 2, wherein the reagent suitable to reducecompound VII is a source of hydrogen.
 11. The process of claim 10,wherein, in addition to the source of hydrogen, the compound VII istreated with a catalyst selected from: palladium on carbon, palladiumoxide, platinum on carbon, Wilkinson's catalyst(chlorotris(triphenylphosphine)rhodium(I)), and any combination thereof.12. The process of claim 3, wherein the reagent suitable to reducecompound VIIb is a source of hydrogen.
 13. The process of claim 12,wherein, in addition to the source of hydrogen, the compound VIIb istreated with a catalyst selected from: palladium on carbon, palladiumoxide, platinum on carbon, Wilkinson's catalyst(chlorotris(triphenylphosphine)rhodium(I)), and any combination thereof.14. The process of claim 4, wherein the hydroxide base is NaOH.
 15. Theprocess of claim 2, wherein salt 3 is an HCl salt.
 16. The process ofclaim 3, wherein salt 3 is an HCl salt.
 17. The process of claim 5,wherein salt 2 is the same or different as salt
 3. 18. The process ofclaim 5, wherein salt 2 is a TsOH salt.
 19. The process of claim 6,wherein the acid is selected from: p-toluene sulfonic acid,methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroaceticacid, HCI, HBr, and sulfuric acid.
 20. The process of claim 7, whereinthe reagent suitable to reduce compound V is selected from: sodiumborohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.